Contrast agents play an important role in clinical magnetic resonance imaging (MRI). About one third of scans employ a contrast agent and these agents are almost exclusively gadolinium (Gd) based T1 agents that provide positive image contrast. Recently, however, Gd-based agents have been implicated in nephrogenic systemic fibrosis (NSF), a debilitating disorder that affects patients with renal insufficiency. It is hypothesized that Gd dissociated from the contrast agent is a causative factor. For new contrast agents, whether they are non-specific extracellular tracers or targeted molecular imaging agents, the risk of Gd toxicity must be addressed. One approach to this problem is to design better Gd ligands that are more resistant to Gd release. A second approach is to increase the relaxivity (r1), i.e. T1 relaxtion efficacy, of the contrast agent. High relaxivity agents could be given at lower doses, reducing metal ion exposure to the patient. This application combines both approaches synergistically to identify new, stable, high relaxivity contrast agents. Two additional features are required to make this new contrast agent technology broadly applicable today and in the future. First, although the majority of clinical scans today are performed at 1.5 tesla, there is a steady increase in imaging performed at higher fields. T1 relaxivity (positive contrast) typically decreases with increasing field while T2 relaxation (signal loss) becomes more efficient. Successful strategies for increasing r1 at low fields can be detrimental at high fields. New agents should demonstrate improved relaxivity from 1.5T to 7T and higher fields relative to existing contrast media. Second, new applications in molecular imaging require bifunctional molecules: a targeting group like a peptide linked to contrast agent group. New contrast agents should be easily incorporated into molecular imaging probes without loss of their relaxometric properties. The goal of this application is to develop chemically stable contrast agents that provide high relaxivity over a broad range of magnetic fields and that can be readily "plugged in" to targeting groups for molecular imaging. We will synthesize clusters of potent, stable gadolinium-based complexes that can be linked to a targeting group in a single step, and characterize these compounds with respect to relaxivity and stability in vitro (Aim 1). High relaxivity, stable clusters will be assessed in rodent models for gadolinium dissociation and acute toxicity, and will be evaluated in a mouse glioma model for low dose imaging efficacy (Aim 2). As a proof of concept for this technology platform, we will use the stable, high relaxivity clusters identified in Aim 1 and validated in Aim 2 and demonstrate that these reagents can be used to readily prepare peptide-targeted molecular imaging probes (Aim 3). We will use these agents in an in vivo model to benchmark against current state-of-the-art targeted MRI contrast agents. PUBLIC HEALTH RELEVANCE: This project involves developing magnetic resonance imaging (MRI) probe technology. We will produce MRI probes that may be safer than existing probes and which are better suited to take advantage of advances in MRI hardware. The technology that we are developing can be readily used by others to prepare new imaging probes for imaging specific organs or diseases.